AIDS Reviews. 2011;13 234 Evolutionary Mechanisms of Retroviral Persistence James B. Whitney 1 , So-Yon Lim 1 and Mark A. Wainberg 2 1 Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA; 2 McGill University AIDS Centre, Lady Davis Institute-Jewish General Hospital, Montreal and Department of Microbiology and Immunology, and Faculty of Medicine, McGill University, Montreal, Quebec, Canada AIDS Rev. 2011;13:234-9 Correspondence to: James B. Whitney Division of Viral Pathogenesis Beth Israel Deaconess Medical Center Center for Life Sciences, 3 Blackfan Circle Boston, Massachusetts, 02115, USA E-mail: jwhitne2@bidmc.harvard.edu Abstract Retroviruses are known to exhibit remarkable genomic pliancy, a capacity that has been attributed to one or more error prone steps in the viral replication cycle. However, increasing evidence suggests that such error represents a key element in viral survival, as exemplified by studies on virus immune evasion, shifts of cellular tropism, and anatomic compartmentalization, which facilitate persistent virus reservoirs. Understanding the dynamic mechanisms that contribute to the establishment and maintenance of retroviral persistence is critical toward the goal of attaining HIV-1 eradication. (AIDS Rev. 2011;13:234-9) Corresponding author: James B. Whitney, jwhitne2@bidmc.harvard.edu Key words HIV eradication. Antiretroviral therapy. Persistence. Virus evolution. Introduction Pathogens exhibit a wealth of strategies to diversify and evade host immunity as a means of persistence. This is illustrated by the adaptive potential for transmission across species exhibited by Mycobacterium tuberculosis, influenza virus, and hepatitis B virus. However, no pathogen shows greater propensity for persistence than HIV-1 and the closely related simian immunodeficiency virus (SIV), since the very nature and course of lentivirus infection is mani- fested in shifts of nucleotide diversity. This review highlights several interrelated virus mechanisms and host factors that drive rapid viral adaptation and facilitate viral persistence. Replicative dynamics during lentiviral infection High-level replication is one requisite for virus se- quence variation. The acute phase of HIV or SIV infection is characterized by an exponential increase in plasma viral RNA levels 1 . It is agreed that viral genetic variation within HIV-infected humans or SIV-infected monkeys is continuous 2-4 . In this scenario, steady-state virus load, and expanding viral diversity is a function of virus repli- cation dynamics, available target cells, and host immu- nity 2,3,5 . Despite the fact that viremia is controlled to a large degree during set point, virus replication continues unabated throughout the protracted asymptomatic phase and even in the setting of antiretroviral therapy 1-8 . RNA viruses such as HIV-1, by virtue of their replication kinetics and plasticity, are capable of exploring an enor- mous sequence space in relation to other organisms, re- sulting in the generation of a heterogeneous virus swarm in which all possible variants are theoretically represent- ed 9 . However, the number of variants represented pheno- typically is constrained to maintain protein function and by the imposed limits of genome size 6 . Mathematical modeling has estimated that the overall rate of HIV virus production is in the order of 10 10 virions/day and the maximal replication capacity of HIV-1 in vivo is approximately 180 generations per year 10-12 . Approximation of the base pair substitution rate of currently circulating HIV-1 variants is 0.0024 sub- stitutions per nucleotide per year 6 . By comparison, the mutation rate of the mammalian genome is about six orders of magnitude lower 13 . Thus, the majority of mutations that are generated in HIV are deleterious, resulting in the pro- duction of suboptimal phenotypes or noninfectious virus 1 . One important outcome of this diversity is the capac- ity for continuous interaction between the selective host environment and the viral quasispecies. This has serious